In a radiological or nuclear disaster in a populated city, tens of thousands of people could be exposed to life threatening levels of ionizing radiation. Rapid triage of affected individuals will be essential for an effective health care response to such an event. Unfortunately, there is no single accurate and practical test available to determine the level of radiation exposure that a person has received. Clinical measurements are non specific and refined assays for chromosomal aberrations require several days for completion. We hypothesized that genome-wide analysis of expression changes in the peripheral blood (PB) could predict radiation status and distinguish dose levels In irradiated Individuals. Subsequently, we succeeded in developing PB signatures of radiation injury that could predict the radiation status and radiation dose level in mice with 96% accuracy. In parallel, we demonstrated that a PB signature of human radiation exposure developed from patients undergoing total body irradiation was 97% accurate at predicting the radiation status of healthy people, non-irradiated patients and irradiated patients. However, it remains to be seen whether PB signatures of total body irradiation can distinguish individuals who receive heterogeneous radiation exposure, a group that could be numerous in a mass casualty event. We also have not explored the biological significance of the pathways altered by radiation; such pathways could provide the key basis for the development of therapeutics to mitigate radiation injury. We will: 1) Determine if PB signatures of partial body irradiation can be developed as distinct from PB signatures of total body irradiation, 2) Apply high throughput computational methods to identify gene targets and pathways that are altered in hematopoietic cells in response to radiation injury and 3) Test available drugs which modulate pathways altered by radiation as candidate mitigators of radiation injury to the hematopoietic system in a validated radiation model. Our broad objective is to refine the PB signature of radiation injury to encompass those with a heterogeneous exposure and to identify signaling pathways in hematopoietic cells that are responsive to radiation injury as a means to develop pathway specific drugs as mitigators of radiation injury.